CN114028362A - 一种高稳定性姜黄素缓释胶囊及其制备方法 - Google Patents
一种高稳定性姜黄素缓释胶囊及其制备方法 Download PDFInfo
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Abstract
一种高稳定性姜黄素缓释胶囊及其制备方法,属于纳米胶囊技术领域。该胶囊中姜黄素的重量含量≥5%,PHA的重量含量为55~65%,PhaP蛋白的重量含量为30~35%。具体制备步骤为:用有机溶剂溶解PHA和姜黄素原料,得到的混合溶液缓慢滴加至PVA溶液中,再加入助溶剂,脱除有机溶剂,之后离心干燥;加入PhaP蛋白,低速搅拌后,低温高速离心,收集沉淀并冷冻干燥,即得姜黄素缓释胶囊。本发明所制备的姜黄素缓释胶囊具有缓释和稳定性好的优势,可广泛应用于食品、药品和保健品中。
Description
技术领域
本发明属于纳米胶囊技术领域,具体涉及一种高稳定性姜黄素缓释胶囊及其制备方法。
背景技术
姜黄素(Curcumin,Cur)来源于姜科植物郁金、姜黄、莪术等的块根或根茎,是天然可食用的东方香料。在中国,姜黄是一种常用中药,其药性辛、苦、大寒,无毒。姜黄素除抗氧化、抗炎、抗纤维化、清除自由基及抗癌等药用价值外,还来源广、便宜易得、毒性低等优点。然而,姜黄素在水中的溶解性差和化学不稳定性限制了其使用,故通过改变剂型来提高姜黄素的吸收特性和稳定性成为近年来的主要研究方向。
CN 111888341A公开了一种姜黄素纳米颗粒及其制备方法,利用BSG蛋白的包封特性,制备了一种姜黄素纳米颗粒,被包裹的姜黄素溶解度、热稳定性和紫外辐照稳定性显著提高,颗粒尺寸范围173.8-233.5nm。
CN 111657415A公开了一种姜黄素纳米颗粒及其制备方法和应用,以姜黄素为芯材,阿拉伯胶和玉米醇溶蛋白为壁材;所述芯材与壁材的质量比为5.5-7.5:100;所述阿拉伯胶和玉米醇溶蛋白的质量比为1-5:5。制成的姜黄素纳米颗粒可拥有制备延缓衰老的饮料。
CN 103446057B公开了一种姜黄素口服纳米粒及其制备方法,该姜黄素纳米粒是由牛磺胆酸和肝素、姜黄素以酞胺键相连接的三元共轭物自组装而成的,姜黄素在纳米粒的核心,而亲水的牛磺胆酸在纳米粒的表面。该发明提供的姜黄素口服纳米粒克服了姜黄素水溶性差的缺点,而且利用牛磺胆酸与小肠的胆汁酸转运体的相互作用,增加药物的吸收,可以克服口服姜黄素生物利用度低的缺点。
虽然通过制剂化技术可将姜黄素制备成胶囊、纳米乳液、固体分散体等不同类型的制剂,但现有技术中对于姜黄素制剂的研究多局限于稳定性、生物利用度等方面,而对于具有缓释效果的姜黄素纳米胶囊的研究还比较少。
发明内容
为解决上述技术问题,本发明提供一种高稳定性姜黄素缓释胶囊及其制备方法,利用高分子材料聚羟基脂肪酸酯(polyhydroxyalkanoate,PHA) 包裹姜黄素,并在其外围通过蛋白展示技术连接上促进水溶性的PHA表面结合蛋白PhaP,来制备具有缓释和高稳定性的PHA-姜黄素-PhaP蛋白的纳米胶囊。具体技术方案是:
一种高稳定性姜黄素缓释胶囊,其中姜黄素的重量含量≥5%,PHA的重量含量为55~65%,PhaP蛋白的重量含量为30~35%,3种成分的重量含量总和为100%。
所述胶囊粒径≤400nm,姜黄素释放率达到90%的时间≥380h。
上述高稳定性姜黄素缓释胶囊的制备方法,包括以下步骤:
(1)PHA包覆:用有机溶剂溶解PHA和姜黄素原料,得到的混合溶液缓慢滴加至PVA溶液中,再加入助溶剂,脱除有机溶剂,之后离心干燥,得到的固体粉末Ⅰ称之为Cur@PHA微球;
(2)PhaP蛋白包覆:取上述Cur@PHA微球,加入PhaP蛋白,低速搅拌后,低温高速离心,收集沉淀并冷冻干燥,得到的固体粉末Ⅱ称之为Cur@PHA-PhaP微球,即为姜黄素缓释胶囊。
所述步骤(1)中,用有机溶剂溶解PHA和姜黄素原料的具体步骤为:将PHA和有机溶剂按照1g:100~160mL混合,于30~35℃加热溶解;姜黄素原料和有机溶剂按照1g:800~1000mL混合;将得到的两种溶液合并得到混合溶液。
所述步骤(1)中,有机溶剂为二氯甲烷,姜黄素原料和PHA的质量比为1:25,所述姜黄素原料中总姜黄素含量为80~95%。
所述步骤(1)中,得到的混合溶液缓慢滴加至质量分数为1%的PVA溶液中,边滴加边搅拌,然后加入助溶剂吐温-20超声混匀1~2h,超声功率为300~570W,脱除有机溶剂,之后离心干燥,得到固体粉末Ⅰ;PVA溶液与姜黄素原料的体积质量比为10mL:1mg,助溶剂与姜黄素原料的体积质量比为0.25mL:1mg。
所述步骤(2)中,PhaP蛋白为浓度1.0~2.0mg/mL的PBS缓冲溶液,缓冲溶液与固体粉末Ⅰ的体积质量比为2mL:1mg。
所述步骤(2)中,低速搅拌的转速为30~60rpm/min,搅拌时间为12~18h。
所述步骤(2)中,低温高速离心的温度≤5℃,离心转速为10000~12000rpm/min,离心时间为20~30min。
本发明姜黄素缓释胶囊是按照图1所示进行组装的,在疏水材料PHA的包覆下,姜黄素嵌入到PHA纳米球的多孔结构中,最后通过强疏水作用力使PhaP蛋白分子又吸附在PHA纳米球的外围。通过PHA和外围蛋白的包裹,姜黄素被完全载到疏水核心,这样的结构使得姜黄素具有较稳定的性质。同样,当胶囊进行释放的时候,也是外围的蛋白先被水解掉,这样附着在PHA上的姜黄素按从外到内的顺序逐级被释放出来,当PHA完全降解掉,其上的姜黄素也全部被释放出来。
采用上述技术方案的有益效果在于:
(1)本发明姜黄素缓释胶囊制备过程中,加入表面活性剂吐温-20可以使制得的多数纳米胶囊粒径集中在80-100nm,微球表面粗糙,基本呈球形,其为纳米级颗粒,大大提高了生物利用度。
(2)姜黄素缓释胶囊外层连接上水溶性的PhaP蛋白,水分散性良好,扩大了姜黄素的应用领域。
(3)姜黄素缓释胶囊经过PHA和PhaP蛋白双层包裹,姜黄素的血清和光稳定性明显优于普通的姜黄素,还使姜黄素达到很好的缓释效果,可广泛应用于食品、药品和保健品中。
本发明制备的姜黄素缓释胶囊粒径≤400nm,姜黄素含量≥5%,光稳定性>85%,姜黄素释放率达到90%的时间≥380h。
附图说明
图1为本发明姜黄素缓释胶囊分子的组装示意图;
图2为实施例1姜黄素缓释胶囊的扫描电镜图;
图3为实施例1姜黄素缓释胶囊的透射电镜图;
图4为实施例1姜黄素缓释胶囊中姜黄素的释放率示意图。
具体实施方式
实施例1
准确称取50mgPHA,用8mL二氯甲烷于30℃加热溶胀,最终溶解。准确称取姜黄素原料2mg,用2mL二氯甲烷溶解。得到的两种溶液合二为一,将该混合液边滴加边搅拌缓慢的融入到20mL质量分数为1%的PVA溶液中,然后加入0.5mL吐温-20。随后,将得到的混合溶液用超声仪器以400W的功率超声1h后,立即使用旋蒸仪,35℃的条件下进行旋蒸,除去二氯甲烷。收集旋蒸后的液体,12000rpm/min离心20min,收集沉淀并用蒸馏水洗涤3次,然后用冷冻干燥机或真空干燥仪进行干燥,得到的固体粉末保存待用。
取1mg上述固体粉末,加入2mL PhaP蛋白的PBS缓冲溶液(浓度为1.2mg/mL),4℃、30rpm/min搅拌结合12h。然后,4℃、12000rpm/min,离心20min,收集沉淀,冷冻干燥后即得姜黄素缓释胶囊。
实施例2
准确称取50gPHA,用8L二氯甲烷于35℃加热溶胀,最终溶解。准确称取姜黄素原料2g,用2L二氯甲烷溶解。得到的两种溶液合二为一,将该混合液边滴加边搅拌缓慢的融入到20L质量分数为1%的PVA溶液中,然后加入0.5L吐温-20。随后,将得到的混合溶液用超声仪器以570W的功率超声1.5h后,立即使用旋蒸仪,35℃的条件下进行旋蒸,除去二氯甲烷。收集旋蒸后的液体,12000rpm/min离心20min,收集沉淀并用蒸馏水洗涤3次,然后用冷冻干燥机或真空干燥仪进行干燥,得到的固体粉末保存待用。
取1g上述固体粉末,加入2L PhaP蛋白的PBS缓冲溶液(浓度为1.2mg/mL),4℃、60rpm/min搅拌结合18h。然后,4℃、10000rpm/min,离心20min,收集沉淀,冷冻干燥后即得姜黄素缓释胶囊。
实施例3
准确称取50mgPHA,用8mL二氯甲烷于35℃加热溶胀,最终溶解。准确称取姜黄素原料2mg,用2mL二氯甲烷溶解。得到的两种溶液合二为一,将该混合液边滴加边搅拌缓慢的融入到20mL质量分数为1%的PVA溶液中,然后加入0.5mL吐温-20。随后,将得到的混合溶液用超声仪器以350W的功率超声2h后,立即使用旋蒸仪,35℃的条件下进行旋蒸,除去二氯甲烷。收集旋蒸后的液体,10000rpm/min离心20min,收集沉淀并用蒸馏水洗涤3次,然后用冷冻干燥机或真空干燥仪进行干燥,得到的固体粉末保存待用。
取1mg上述固体粉末,加入2mL PhaP蛋白的PBS缓冲溶液(浓度为1.3mg/mL),4℃、60rpm/min搅拌结合15h。然后,4℃、12000rpm/min,离心20min,收集沉淀,冷冻干燥后即得姜黄素缓释胶囊。
实施例4
准确称取100gPHA,用10L二氯甲烷于33℃加热溶胀,最终溶解。准确称取姜黄素原料4g,用3.5L二氯甲烷溶解。得到的两种溶液合二为一,将该混合液边滴加边搅拌缓慢的融入到40L质量分数为1%的PVA溶液中,然后加入1L吐温-20。随后,将得到的混合溶液用超声仪器以450W的功率超声1.5h后,立即使用旋蒸仪,36℃的条件下进行旋蒸,除去二氯甲烷。收集旋蒸后的液体,11000rpm/min离心25min,收集沉淀并用蒸馏水洗涤2次,然后用冷冻干燥机或真空干燥仪进行干燥,得到的固体粉末保存待用。
取2g上述固体粉末,加入4L PhaP蛋白的PBS缓冲溶液(浓度为2.0mg/mL),3℃、40rpm/min搅拌结合17h。然后,3℃、11000rpm/min,离心20min,收集沉淀,冷冻干燥后即得姜黄素缓释胶囊。
实施例5
准确称取1gPHA,用12mL二氯甲烷于36℃加热溶胀,最终溶解。准确称取姜黄素原料40mg,用38mL二氯甲烷溶解。得到的两种溶液合二为一,将该混合液边滴加边搅拌缓慢的融入到400mL质量分数为1%的PVA溶液中,然后加入10mL吐温-20。随后,将得到的混合溶液用超声仪器以300W的功率超声1.5h后,立即使用旋蒸仪,34℃的条件下进行旋蒸,除去二氯甲烷。收集旋蒸后的液体,10000rpm/min离心30min,收集沉淀并用蒸馏水洗涤3次,然后用冷冻干燥机或真空干燥仪进行干燥,得到的固体粉末保存待用。
取10mg上述固体粉末,加入20mLPhaP蛋白的PBS缓冲溶液(浓度为1.6mg/mL),5℃、55rpm/min搅拌结合16h。然后,5℃、10500rpm/min,离心30min,收集沉淀,冷冻干燥后即得姜黄素缓释胶囊。
实施例6
准确称取1gPHA,用15mL二氯甲烷于37℃加热溶胀,最终溶解。准确称取姜黄素原料40mg,用32mL二氯甲烷溶解。得到的两种溶液合二为一,将该混合液边滴加边搅拌缓慢的融入到400mL质量分数为1%的PVA溶液中,然后加入10mL吐温-20。随后,将得到的混合溶液用超声仪器以520W的功率超声1h后,立即使用旋蒸仪,34℃的条件下进行旋蒸,除去二氯甲烷。收集旋蒸后的液体,11000rpm/min离心20min,收集沉淀并用蒸馏水洗涤3次,然后用冷冻干燥机或真空干燥仪进行干燥,得到的固体粉末保存待用。
取10mg上述固体粉末,加入20mLPhaP蛋白的PBS缓冲溶液(浓度为1.0mg/mL),2℃、55rpm/min搅拌结合13h。然后,2℃、11500rpm/min,离心25min,收集沉淀,冷冻干燥后即得姜黄素缓释胶囊。
取实施例1~6所得的姜黄素缓释胶囊、姜黄素原料进行形态观察和性能测试,具体操作如下:
1、形态、粒径观察
取实施例1-6的胶囊样品和姜黄素原料,用透射电镜观察形态和粒径。
2、水溶性分散情况
分别称取0.02g实施例1-6的胶囊样品和姜黄素原料,分散于10ml水中,观察在水中的分散情况。
姜黄素原料不溶于水,呈浅黄绿色。
实施例1-6的姜黄素缓释胶囊样品在水中的分散性良好,无明显聚团沉淀,为分散均匀的乳浊液形式。
3、包封率和载药量
为了确定姜黄素缓释胶囊装载姜黄素的能力,采用外标法,描绘标准曲线,通过如下公式计算包封率和载药量。
包封率(EE)=(姜黄素的总投入量-上清液中残余的姜黄素量)÷姜黄素的总投入量×100%;
载药量(DL)=(姜黄素的总投入量-上清液中残余的姜黄素量)÷姜黄素缓释胶囊总重量×100%;
姜黄素的总投入量=姜黄素原料的投入重量×其中总姜黄素含量;
上清液中残余的姜黄素量=上清液的体积×上清液中姜黄素含量;
上清液:指步骤(2)中,低温高速离心后的上清液;
载药量(DL):即姜黄素缓释胶囊中姜黄素的重量含量。
4、稳定性分析
(1)血清稳定性:模拟体内环境对姜黄素缓释胶囊进行稳定性的测定。将姜黄素缓释胶囊与PBS水溶液按照质量体积比为1mL:1mg混合,得到的溶液与等体积的含10%非加热灭活的胎牛血清的细胞培养液混合,并在37°C下进行孵育。分别孵育1h、2h、4h、8h和12h,取上述混合物采用HPLC分析是否有姜黄素释放出来。
(2)光稳定性:分别在体外对姜黄素原料及姜黄素缓释胶囊进行光稳定性验证。配制1mg/mL姜黄素溶液,即取15mg姜黄素加入15ml甲醇,于室内阳光照射下放置2d后取样品,用紫外分光光度计测定姜黄素含量(10μl姜黄素溶液加3ml甲醇),检测波长为425nm。将姜黄素缓释胶囊置于室内阳光照射下,放置2d后取一定粉末溶于氯仿,使其内包裹的姜黄素释放出来,同时用紫外分光光度计测定姜黄素含量,计算含量保留率。
5、姜黄素的释放测定
采用透析袋透析的方法,将1mL姜黄素缓释胶囊的水溶液(姜黄素终浓度100µM)移入透析袋(MWCO 10kDa)中,在pH 值4.5的醋酸-醋酸钠缓冲液中,37℃恒温孵育,孵育0、2、4、6、8、12、24、48、72、96、120、144、168、192、216、240、264、288、312、336、360和384h,每个时间点依次取出500µL的混合物,每次取完后均补加500µL pH 值4.5的醋酸-醋酸钠的缓冲液。将取出的溶液分别使用高效液相色谱仪进行检测,通过姜黄素标准曲线依次计算出对应浓度。通过如下公式计算姜黄素的释放率。记录姜黄素释放达到90%时的时间,分析姜黄素缓释胶囊的体外释放行为。
某一时间点的释放率=该时间点时缓冲液中姜黄素的总重量÷透析袋中姜黄素初始时的总重量×100%
表1.实施例1-3姜黄素缓释胶囊性能检测结果对比
表2. 姜黄素与实施例4-6姜黄素缓释胶囊性能检测结果对比
通过表格可以看出:实施例1-6所得姜黄素缓释胶囊均为纳米级颗粒,多数胶囊的粒径集中在80-100nm之间,基本呈球状,在水中的分散性较好,在血清溶液未观察到明显变化,稳定性较好,光稳定性明显优于普通的姜黄素,还可使姜黄素达到很好的缓释作用。
Claims (9)
1.一种高稳定性姜黄素缓释胶囊,其特征在于,所述胶囊中姜黄素的重量含量≥5%,PHA的重量含量为55~65%,PhaP蛋白的重量含量为30~35%,3种成分的重量含量总和为100%。
2.根据权利要求1所述的高稳定性姜黄素缓释胶囊,其特征在于,所述胶囊粒径≤400nm,姜黄素释放率达到90%的时间≥380h。
3.基于权利要求1或2所述的高稳定性姜黄素缓释胶囊的制备方法,其特征在于,包括以下步骤:
(1)PHA包覆:用有机溶剂溶解PHA和姜黄素原料,得到的混合溶液缓慢滴加至PVA溶液中,再加入助溶剂,脱除有机溶剂,之后离心干燥,得到的固体粉末Ⅰ称之为Cur@PHA微球;
(2)PhaP蛋白包覆:取上述Cur@PHA微球,加入PhaP蛋白,低速搅拌后,低温高速离心,收集沉淀并冷冻干燥,得到的固体粉末Ⅱ称之为Cur@PHA-PhaP微球,即为姜黄素缓释胶囊。
4.根据权利要求3所述的高稳定性姜黄素缓释胶囊的制备方法,其特征在于,所述步骤(1)中,用有机溶剂溶解PHA和姜黄素原料的具体步骤为:将PHA和有机溶剂按照1g:100~160mL混合,于30~35℃加热溶解;姜黄素原料和有机溶剂按照1g:800~1000mL混合;将得到的两种溶液合并得到混合溶液。
5.根据权利要求4所述的高稳定性姜黄素缓释胶囊的制备方法,其特征在于,所述步骤(1)中,有机溶剂为二氯甲烷,姜黄素原料和PHA的质量比为1:25,所述姜黄素原料中总姜黄素含量为80~95%。
6.根据权利要求5所述的高稳定性姜黄素缓释胶囊的制备方法,其特征在于,所述步骤(1)中,得到的混合溶液缓慢滴加至质量分数为1%的PVA溶液中,边滴加边搅拌,然后加入助溶剂吐温-20超声混匀1~2h,超声功率为300~570W,脱除有机溶剂,之后离心干燥,得到固体粉末Ⅰ;PVA溶液与姜黄素原料的体积质量比为10mL:1mg,助溶剂与姜黄素原料的体积质量比为0.25mL:1mg。
7.根据权利要求6所述的高稳定性姜黄素缓释胶囊的制备方法,其特征在于,所述步骤(2)中,PhaP蛋白为浓度1.0~2.0mg/mL的PBS缓冲溶液,缓冲溶液与固体粉末Ⅰ的体积质量比为2mL:1mg。
8.根据权利要求7所述的高稳定性姜黄素缓释胶囊的制备方法,其特征在于,所述步骤(2)中,低速搅拌的转速为30~60rpm/min,搅拌时间为12~18h。
9.根据权利要求1-8任一项所述的高稳定性姜黄素缓释胶囊的制备方法,其特征在于,所述步骤(2)中,低温高速离心的温度≤5℃,离心转速为10000~12000rpm/min,离心时间为20~30min。
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